New 5-Aminoisophthalic Acid Derivatives, Salts And Esters Thereof And Methods For Their Preparation

ABSTRACT

The invention relates to a series of new compounds of the general formula I:     in which R4 and X are as defined above and the -COOE group is an   or an ester thereof, in which R3, R4 and X are as defined before and -COY is a reactive derivative of a carboxylic group, preferably a lower alkyl ester group, with an amine R1R2NH in which R1 and R2 are as defined above. The starting materials of formula II are new compounds. In one method for the preparation of these new compounds 4chloroisophthalic acid is used as starting material. By nitration of this compound a nitro group is introduced in the 5-position. After esterification of the two free carboxylic acid groups and treatment with R4-X-H, in which R4 and X are as defined, the R4X radical replaces the chlorine atom in the 4-position, forming an alkyl 4-R4X-5-nitroisophthalate. The R4X radical can in the same manner be introduced in the corresponding free acids as well, whereafter an esterification is performed, if desired. Thereafter the nitro group is reduced into an amino group in known manner to yield an alkyl 4-R4X-5-aminoisophthalate. A catalytic reduction for instance with palladium-on-carbon as catalyst under slightly alkaline conditions, or ferrosulfate in ammonium hydroxide can be mentioned as suitable reducing agents, but other known methods can be used as well. In the case where the free isophthalic acid derivatives are obtained, these are transformed to the desired corresponding di-esters in known manner. By a partial saponification process by means of for instance the calculated amount of alkali hydroxide in ethanol the ester is partly saponified to a 4-R4X-3-amino-5-carbalkoxybenzoic acid of the formula IV:     in which X is selected from the group consisting of -O-, -S-, and -NH-; R1 is selected from the group consisting of hydrogen and aliphatic radicals with from one to four carbon atoms; R2 is selected from the group consisting of hydrogen, saturated and unsaturated, straight and branched aliphatic radicals with from one to six carbon atoms, and aryl- and heterocyclic-substituted aliphatic radicals with from one to four carbon atoms; R3 is selected from the group consisting of saturated and unsaturated, straight and branched aliphatic radicals with from one to six carbon atoms, and aryl- and heterocyclic-substituted aliphatic radicals with from one to four carbon atoms, and R4 is selected from the group consisting of unsubstituted and substituted phenyl radicals. In particular, a straight or branched, saturated or unsaturated, aliphatic radical means e.g., a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert. butyl radical, or one of the different isomeric pentyl or hexyl radicals, an alkenyl or alkynyl radical, e.g., a vinyl, allyl or propargyl radical. In the aromatically or heterocyclically substituted aliphatic radicals, the aromatic part of the radical can be a mono- or bicyclic aryl radical, e.g., a phenyl or naphthyl radical, the heterocyclic part of the radical can be a mono- or bicyclic radical containing one or more oxygen, sulphur and nitrogen atoms as ring members, e.g., 2-, 3or 4-pyridyl, 2- or 3-furyl or -thienyl, thiazolyl, imidazolyl, benzimidazolyl, and the corresponding hydrogenated ringsystems, and the aliphatic part of the radicals can contain 1 to 4 carbon atoms. Illustrative examples of such aromatically or heterocyclically substituted aliphatic radicals are benzyl, 1- Or 2-phenethyl, 1- or 2-naphthylmethyl, furylmethyl and the corresponding ethyl, propyl and butyl radicals. The salts of the compounds are pharmaceutically acceptable salts, such as alkali metal salts, alkaline earth metal salts, the ammonium salt or organic amine salts, e.g., mono-, di-, or trialkylamine salts, mono-, di-, or trialkanolamine salts, or cyclic amine salts. The esters of the compounds of formula I are particularly esters with lower alkanols, e.g., methanol or ethanol the different isomers of propanols and butanols, and substituted alkanols, e.g., cyanomethanol, or aryl-lower alkanols, e.g., benzylalcohol or phenylethanol. The above mentioned radicals R1 to R4 can be further substituted with hydroxy, alkyl, or alkoxy groups with from one to four carbon atoms, with halogen atoms, preferably fluorine, chlorine or bromine, or haloalkyl groups, e.g., a trifluoromethyl group. Whenever the expression &#39;&#39;&#39;&#39;lower&#39;&#39;&#39;&#39; is used in the present specification it stands for a radical containing from one to six carbon atoms. Many sulfamylbenzoic acid derivatives are known to possess diuretic activity. It has hitherto been generally held that the diuretic and saluretic activities of these benzoic acid derivatives are closely related to the presence of at least one sulfonamide group. It is therefore very surprising that the 5aminoisophthalic acid derivatives of the present invention have pronounced diuretic and saluretic activity with rapid onset of effect and high electrolyte excretion level. In experiments on dogs it has been shown that the present compounds are effective in doses less than 1 mg/kg, which means that they are at least as effective as the well-known diuretic furosemide, even if no sulfonamide group is present. The absence of the sulfonamide group and the particular structure of the compounds make them interesting also because allergic manifestations caused by prolonged use of the well known sulphonamide containing diuretics may be avoided by using the new compounds of the invention. This in connection with a very low toxicity makes the compounds of the present invention especially valuable from a therapeutic point of view in the treatment of different kinds of oedematous and hypertensive conditions where it is desirous to relieve excessive water and salt retension, e.g., in connection with heart and kidney diseases. The present compounds are effective after oral, enteral or parenteral administration, and are preferably prescribed in the form of tablets, pills, dragees, or capsules containing the free acid or salts thereof with atoxic bases, or the esters or amides thereof, mixed with carriers and/or auxiliary agents. Pharmaceutical organic or inorganic, solid or liquid carriers suitable for oral, enteral or parenteral administration can be used to make up compositions containing the present compounds. Gelatine, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gum, polyalkylene glycol, or other known carriers for medicaments are all suitable as carriers. The compositions may further contain other therapeutic compounds applied in the treatment of, for example oedemas and hypertension, besides the well known auxiliary agents. Such other compounds may be, for instance, Veratrumor Rauwolfia alkaloids, e.g., reserpine, rescinnamine or protoveratrine or synthetic hypotensive compounds, e.g., hydralazine, or other diuretics and saluretics, such as the well-known benzothiadiazines, e.g., hydroflumethiazide, bendroflumethiazide, and the like. Potassiumsparing diuretics, e.g., triamterene, may also be used in the preparation of the compositions. For some purposes it may be desirable to add small amounts of carboanhydrase inhibitors or aldosterone antagonists, e.g., spironolactone. Salts, which are soluble in water, may with advantage be administered by injection. The pharmaceutical preparations are useFul in the treatment of oedematous conditions, e.g., cardiac, hepatic, renal, lung and brain oedema, or oedematous conditions during pregnancy, and of pathological conditions which produce an abnormal retension of the electrolytes of the body, and in the treatment of hypertension. The parenteral preparations are in particular useful in the treatment of conditions in which a quick dehydration is desirable, e.g., in the intensive therapy in the case of oedemas in the lung. In the continuous therapy of patients suffering from e.g., hypertension, the tablets or capsules may be the appropriate form of pharmaceutical preparation owing to the prolonged effect obtained when the drug is given orally, in particular in the form of sustained-release tablets. In the treatment of heart failure and hypertension such tablets may advantageously contain other active components, as specified hereinbefore. The compounds of the invention can be prepared by various methods. In one embodiment a compound of formula II: or an ester thereof, in which X, R1, R2 and R4 are as defined above, is subjected to an alkylation process to form the compounds of formula I. This alkylation can be performed by a reaction with an alkylating agent of the formula R3-X&#39;&#39;, in which R3 is as defined above and X&#39;&#39; stands for halogen, preferably chlorine or bromine, or a hydroxy group, a hydroxysulfonyloxy group, an R3oxysulfonyloxy group, or an alkyl- or arylsulfonyloxy group. The reaction can be performed in an alcoholic solvent in which case the corresponding ester of the compound of formula I can be formed simultaneously. If desired, the esters can be hydrolyzed to the corresponding free acids and vice versa in known manner. If desired, the R3 substituent can also be introduced by a wellknown reductive alkylation process by means of the appropriate aldehyde. In another embodiment the compounds of the invention can be prepared by treating a compound of formula III: in which X is selected from the group consisting of -O-, -S-, and -NH-; R1 is selected from the group consisting of hydrogen and aliphatic radicals with from one to four carbon atoms; R2 is selected from the group consisting of hydrogen, saturated and unsaturated, straight and branched aliphatic radicals with from one to six carbon atoms, and aryl- and heterocyclic-substituted aliphatic radicals with from one to four carbon atoms; R3 is selected from the group consisting of saturated and unsaturated, straight and branched aliphatic radicals with from one to six carbon atoms, and aryl- and heterocyclic-substituted aliphatic radicals with from one to four carbon atoms, and R4 is selected from the group consisting of unsubstituted and substituted phenyl radicals; to salts and esters of these compounds and to methods for their preparation. The present 5-aminoisophthalic acid derivatives have pronounced diuretic and saluretic activity with rapid onset of effect and high electrolyte excretion level. This invention relates to a series of new compounds, which are derived from 5-aminoisophthalic acid (3-amino-5-carboxybenzoic acid), to salts and esters of these compounds and to methods for the preparation of the new compounds. The compounds have the general formula I:

United States Patent [191 Feit et al.

[ 1 3,864,385 Feb. 4, 1975 [75] Inventors: Peter Werner Feit; Herta Bruun,

both of Graested, Denmark [73] Assignee: Lovens Kemiske Fabrik Produktionsaktieselskab, Ballerup, Denmark 22 Filed: Sept. 27, 1972 21 Appl. No.: 292,525

[30] Foreign Application Priority Data Oct. 5, 1971 Great Britain 46291/71 Dec. 14, 1971 Great Britain 58100/71 [52] US. Cl. 260/470, 260/290 R, 260/302 R, 260/309.6, 260/327 R, 260/347.4, 260/471 R, 260/516, 260/518 R, 260/519 Primary Examiner-Lorraine A. Weinberger Assistant Examiner-Paul J. Killos Attorney, Agent, or Firm-Jackson, Jackson & Chovanes [57] ABSTRACT The invention relates to a series of new compounds of the general formula I:

in which X is selected from the group consisting of O, S, and NH-; R is selected from the group consisting of hydrogen and aliphatic radicals with from one to four carbon atoms; R is selected from the group consisting of hydrogen, saturated and unsaturated, straight and branched aliphatic radicals with from one to six carbon atoms, and aryland heterocyclic-substituted aliphatic radicals with from one to four carbon atoms; R is selected from the group consisting of saturated and unsaturated, straight and branched aliphatic radicals with from one to six carbon atoms, and aryland heterocyclic-substituted aliphatic radicals with from one to four carbon atoms, and R is selected from the group consisting of unsubstituted and substituted phenyl radicals; to salts and esters of these compounds and to methods for their preparation.

The present 5-aminoisophthalic acid derivatives have pronounced diuretic and saluretic activity with rapid onset of effect and high electrolyte excretion level.

7 Claims, No Drawings 1 NEW S-AMINOISOPHTHALIC ACID DERIVATIVES, SALTS AND ESTERS THEREOF AND METHODS FOR THEIR PREPARATION This invention relates to a series of new compounds, which are derived from S-aminoisophthalic acid (3-amino-5-carboxybenzoic acid), to salts and esters of these compounds and to methods for the preparation of the new compounds. The compounds have the general formula I:

I |ll-l-R RAX .RZ 1

N-C COOl. 1 ii in which X is selected from the group consisting of O-, -S, and -Nl-l-; R, is selected from the group consisting of hydrogen and aliphatic radicals with from one to four carbon atoms; R is selected from the group consisting of hydrogen, saturated and unsaturated, straight and branched aliphatic radicals with from one to six carbon atoms, and aryland heterocyclic-substituted aliphatic radicals with from one to four carbon atoms; R, is selected from the group consisting of saturated and unsaturated, straight and branched aliphatic radicals with from one to six carbon atoms, and aryland heterocyclic-substituted aliphatic radicals with from one to four carbon atoms, and R is selected from the group consisting of unsubstituted and substituted phenyl radicals.

In particular, a straight or branched, saturated or unsaturated, aliphatic radical means e.g., a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert. butyl radical, or one of the different isomeric pentyl or hexyl radicals, an alkenyl or alkynyl radical, e.g., a vinyl, allyl or propargyl radical. ln the aromatically or heterocyclically substituted aliphatic radicals, the aromatic part of the radical can be a monoor bicyclic aryl radical, e.g., a phenyl or naphthyl radical, the heterocyclic part of the radical can be a monoor bicyclic radical containing one or more oxygen, sulphur and nitrogen atoms as ring members, e.g., 2-, 3- or 4-pyridyl, 2- or 3-furyl or -thienyl, thiazolyl, imidazolyl, benzimidazolyl, and the corresponding hydrogenated ringsystems, and the aliphatic part of the radicals can contain 1 to 4 carbon atoms. Illustrative examples of such aromatically or heterocyclically substituted aliphatic radicals are benzyl, lor 2-phenethyl, 1- or Z-naphthylmethyl, furylmethyl and the corresponding ethyl, propyl and butyl radicals. The salts of the compounds are pharmaceutically acceptable salts, such as alkali metal salts, alkaline earth metal salts, the ammonium salt or organic amine salts, e.g., mono-, di-, or trialkylamine salts, mono-, di-, or trialkanolamine salts, or cyclic amine salts.

The esters of the compounds of formula I are particularly esters with lower alkanols, e.g., methanol or ethanol the different isomers of propanols and butanols, and substituted alkanols, e.g., cyanomethanol, or aryllower alkanols, e.g., benzylalcohol or phenylethanol.

The above mentioned radicals R, to R4 can be further substituted with hydroxy, alkyl, or alkoxy groups with from one to four carbon atoms, with halogen atoms,

preferably fluorine, chlorine or bromine, or haloalkyl groups, e.g., a trifluoromethyl group.

Whenever the expression lower" is used in the present specification it stands for a radical containing from one to six carbon atoms.

Many sulfamylbenzoic acid derivatives are known to possess diuretic activity. It has hitherto been generally held that the diuretic and saluretic activities of these benzoic acid derivatives are closely related to the presence of at least one sulfonamide group. It is therefore very surprising that the S-aminoisophthalic acid derivatives ofthe present invention have pronounced diuretic and saluretic activity with rapid onset of effect and high electrolyte excretion level. In experiments on dogs it has been shown that the present compounds are effective in doses less than 1 mg/kg, which means that they are at least as effective as the well-known diuretic furosemide, even if no sulfonamide group is present. The absence of the sulfonamide group and the particular structure of the compounds make them interesting also because allergic manifestations caused by prolonged use of the well known sulphonamide containing diuretics may be avoided by using the new compounds of the invention. This in connection with a very low toxicity makes the compounds of the present invention especially valuable from a therapeutic point of view in the treatment of different kinds of oedematous and hypertensive conditions where it is desirous to relieve excessive water and salt retension, e.g., in connection with heart and kidney diseases.

The present compounds are effective after oral, enteral or parenteral administration, and are preferably prescribed in the form oftablets, pills, dragees, or capsules containing the free acid or salts thereof with atoxic bases, or the esters or amides thereof, mixed with carriers and/or auxiliary agents.

Pharmaceutical organic or inorganic, solid or liquid carriers suitable for oral, enteral or parenteral administration can be used to make up compositions containing the present compounds. Gelatine, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gum, polyalkylene glycol, or other known carriers for medicaments are all suitable as carriers.

The compositions may further contain other therapeutic compounds applied in the treatment of, for example oedemas and hypertension, besides the well known auxiliary agents. Such other compounds may be, for instance, Veratrumor Rauwolfia alkaloids, e.g., reserpine, rescinnamine or protoveratrine or synthetic hypotensive compounds, e.g., hydralazine, or other diuretics and saluretics, such as the well-known benzothiadiazines, e.g., hydroflumethiazide, bendroflumethiazide, and the like. Potassium-sparing diuretics, e.g., triamterene, may also be used in the preparation of the compositions. For some purposes it may be desirable to add small amounts of carboanhydrase inhibitors or aldosterone antagonists, e.g., spironolactone.

Salts, which are soluble in water, may with advantage be administered by injection. The pharmaceutical preparations are useful in the treatment of oedematous conditions, e.g., cardiac, hepatic, renal, lung and brain oedema, or oedematous conditions during pregnancy, and of pathological conditions which produce an abnormal retension of the electrolytes of the body, and in the treatment of hypertension.

The parenteral preparations are in particular useful in the treatment of conditions in which a quick dehydration is desirable, e.g., in the intensive therapy in the case of oedemas in the lung. In the continuous therapy of patients suffering from e.g., hypertension, the tablets or capsules may be the appropriate form of pharmaceutical preparation owing to the prolonged effect obtained when the drug is given orally, in particular inthe form of sustained-release tablets.

In the treatment of heart failure and hypertension such tablets may advantageously contain other active components, as specified hereinbefore.

The compounds of the invention can be prepared by various methods. In one embodiment a compound of formula ll:

or an ester thereof, in which X, R R and R are as defined above, is subjected to an alkylation process to form the compounds of formula l.

This alkylation can be performed by a reaction with an alkylating agent of the formula R X, in which R is as defined above and X stands for halogen, preferably chlorine or bromine, or a hydroxy group, a hydroxysulfonyloxy group, an R -oxysulfonyloxy group, or an alkylor arylsulfonyloxy group. The reaction can be performed in an alcoholic solvent in which case the corresponding ester of the compound of formula I can be formed simultaneously. If desired, the esters can be hydrolyzed to the corresponding free acids and vice versa in known manner.

If desired, the R substituent can also be introduced by a well-known reductive alkylation process by means of the appropriate aldehyde.

In another embodiment the compounds of the invention can be prepared by treating a compound of formula III:

rim-R 11 x I J III YOC/ X coon or an ester thereof, in which R R and X are as defined before and -COY is a reactive derivative ofa carboxylic group, preferably a lower alkyl ester group, with an amine R R NH in which R and R are as defined above.

The starting materials of formula II are new compounds. ln one method for the preparation of these new compounds 4-chloroisophthalic acid is used as starting material. By nitration of this compound a nitro group is introduced in the 5-position. After esterification of the two free carboxylic acid groups and treatment with R X-H, in which R4 and X are as defined, the R X radical replaces the chlorine atom in the 4-position, forming an alkyl 4-R.,X-S-nitroisophthalate.

The R X radical can in the same manner be introduced in the corresponding free acids as well, whereafter an esterification is performed, if desired.

Thereafter the nitro group is reduced into an amino group in known manner to yield an alkyl 4-R X5- aminoisophthalate. A catalytic reduction for instance with palladium-on-carbon as catalyst under slightly alkaline conditions, or ferrosulfate in ammonium hydroxide can be mentioned as suitable reducing agents, but other known methods can be used as well. In the case where the free isophthalic acid derivatives are obtained, these are transformed to the desired corresponding di-esters in known manner.

By a partial saponification process by means of for instance the calculated amount of alkali hydroxide in ethanol the ester is partly saponified to a 4-R4X-3- amino-S-carbalkoxybenzoic acid of the formula W:

N ll

in which R and X are as defined above and the -COOE group is an ester group, preferably an alkyl ester group.

By a treatment with an amine of the formula HNR,R in which R, and R are as defined above, the compounds of formula II are obtained, which as described above are alkylated into the compounds of the invention.

In another method for preparing the starting material of formula ll an alkyl 4-R X-5-nitroisophthalate prepared as described above can be subjected to a partial saponification process with for instance the calculated amount of an alkali hydroxide, whereby an alkyl 4- R4X-5-carboxy-3-nitrobenzoate is obtained. This compound can be converted into the corresponding acid chloride by treatment with e.g., thionyl chloride, the acid chloride afterwards being reacted with an amine NHR R whereby a compound of the formula V:

coon in which R R X and -COOE have the above meaning, is obtained. The compound of formula IV is then saponified to the corresponding acid, in which the nitro group is reduced in a known manner to the starting material of formula 1].

The starting compounds of formula III are obtained from a 4-R X-5-amino-isophthalic acid or esters thereof prepared as described above, by alkylation processes similar to those as described above, esterification and/or saponification processes which can be performed in arbitrary order. If desired, a free carboxylic group in the 3-position is converted to the COY group as the last step by known procedures.

The invention will now be illustrated by the following non-limiting examples from which the dtails of the embodiments will be apparent.

EXAMPLE 1.

3-Amino-4-anilino-5-carbamylbenzoic acid.

A. 4-Chloro-5-nitroisophthalic acid.

To a mixture of concentrated sulfuric acid (190 ml; d 1.8) and concentrated nitric acid (123 ml; d= 1.4) a solution of 4-chloroisophthalic acid (69 g) in warm concentrated sulfuric acid (690 ml; d 1.8) is added with stirring over a period of 1 hour. The temperature is then raised to 110C. and the reaction mixture is stirred for an additional 6 hours. After cooling, the mixture is poured unto ice-water, and the precipitate is collected and washed with water. After recrystallization from aqueous ethanol and drying, the 4-chloro-5- nitroisophthalic acid is obtained with a melting point of 276-277.5C.

B. Diethyl 4-chloro-S-nitroisophthalate.

A solution of 4-chloro-S-nitroisophthalic acid (123 g) in dry ethanol (1200 ml) is saturated with gaseous hydrochloric acid. The reaction mixture is allowed to warm during the inlet of the hydrochloric acid. After standing for 5 hours, the solvent is removed by evaporation in vacuo. The residue is distilled in high vacuo at 0.5 mm Hg to give diethyl 4-chloro-5- nitroisophthalate which has a boiling point of 175C.

C. Diethyl 4-anilino-5-nitroisophthalate.

A mixture ofdiethyl 4-chloro-5-nitroisophthalate (55 g), aniline (51 g and water (180 ml) is refluxed for 5 hours. After cooling the aqueous layer is decanted off and the oily diethyl 4-anilino-S-nitroisophthalate dissolved in boiling 50 percent aqueous ethanol (300 ml) and crystallized by stirring and cooling. After collection and recrystallization from 96 percent ethanol and drying, the compound has a melting point of 9091C.

D. Ethyl 4-anilino-5-carboxy-3-nitrobenzoate.

To a warm solution of diethyl 4-anilino-5- nitroisophthalate (113 g) in 99,9 percent ethanol (500 ml) a solution of potassium hydroxide g, 88 percent) in 90 percent aqueous ethanol (200 ml) is added dropwise by stirring during 2 hours. Then the reaction mixture is refluxed by stirring for 1 hour. After cooling in a refrigerator the precipitated potassium salt of ethyl 4-anilino-5-carboxy-3-nitrobenzoate is collected by suction, washed with ice-cold water (50 ml) and dried.

The crude potassium salt is dissolved in boiling water (2100 ml) and after filtration the acid is precipitated by the addition of acetic acid (150 ml). The acid is collected by suction, washed with water and dried. The melting point is: 273274C. (decomp.).

E. Ethyl 4-anilino-5-chlorocarbonyl-3-nitrobenzoate.

A mixture of ethyl 4-anilino-5-carboxy-3- nitrobenzoate (20 g) and thionylchloride (36 g, 22 ml) is heated to 90C. while stirring for 1 hour. To the cooled mixture cyclohexane/petroleum ether (200 ml, 1:2) is added while stirring to precipitate the ethyl 4- anilino-S-chlorocarbonyl-3-nitrobenzoate. After cooling in a refrigerator, the product is collected by suction, washed with petroleum ether and air-dried. The compound has a melting point of l l6l20C.

F. Ethyl 4-anilino-5-carbamyl-3-nitrobenzoate.

Ethyl 4-anilino-5-chlorocarbonyl-3-nitrobenzoate (24 g) is added in portions to an ice-cooled and vigorously stirred 25 percent aqueous ammonia solution (200 ml). The stirring is continued for l-2 hours.

Crude ethyl 4-anilino -5-carbamyl-3-nitrobenzoate is collected by suction, washed with water, air-dried, and extracted with boiling ethanol (400 ml, 99 percent) while stirring. The extract is diluted with water (400 ml). The compound crystallizes on cooling. It has a melting point of 201-202C. (decomp.).

G.- 4-Anilino-5-carbamyl-3-nitrobenzoic acid.

A suspension of ethyl 4-anilino-5-carbamyl-3- nitrobenzoate (6.5 g) in water ml) containing aqueous sodium hydroxide solution (20 ml, 1 N) and ethanol (10 ml) is refluxed for 1 hour while stirring. After cooling acetic acid is added to precipitate 4- anilino-S-carbamyl-3-nitrobenzoic acid which is collected by suction. After recrystallization from acetic acid/water the compound has a melting point of 273274C. (decomp.).

H. 3-Amino-4-anilino-5-carbamylbenzoic acid.

4-Ani1ino-5-carbamyl-3-nitrobenzoic acid (6 g) is dissolved in l N sodium hydroxide solution (20 ml) and water (200 ml) and hydrogenated after addition of a palladium-on-carbon catalyst (0.5 g catalyst, containing 10 percent Pd). When the hydrogen uptake becomes negligible, the catalyst is removed by filtration and the 3-amino -4-anilino-5-carbamylbenzoic acid precipitated from the filtrate by addition of acetic acid until pH 4-3. After recrystallization from ethanol the melting point is 25 l252C. (decomp.).

EXAMPLE 2.

Ethyl 4-anilino-5-carboxy-3-nitrobenzoate.

A. 4-Anilino-5-nitroisophthalic acid.

A mixture of diethyl 4-anilino-5-nitroisophthalate (77 g), 1 N sodium hydroxide (450 ml) and water (800 ml) is refluxed while stirring until a clear solution is obtained. The 4-anilino-5-nitroisophthalic acid is precipitated by addition of 4 N hydrochloric acid. After recrystallization from 50 percent aqueous ethanol and drying, the compound has a melting point of 284C. (decomp.).

B. Ethyl 4-anilino-5-carboxy-3-nitrobenzoate.

To a slight warm solution of 4-anilino-5- nitroisophthalic acid (10 g) in 99.9 percent ethanol (250 ml) a saturated solution of gaseous hydrochloric acid in 99.9 percent ethanol (200 ml) is added. The mixture is allowed to stand at room temperature for 16 hours. The precipitated ethyl 4-anilino-5-carboxy-3- nitrobenzoate is collected by suction. It has a melting point of 273274C. (decomp.).

EXAMPLE 3 3-Amino-4-anilino-5-methylcarbamyl-benzoic acid.

A. Ethyl 4-anilino-5-methylcarbamyl-3- nitrobenzoate.

By substituting 35 percent aqueous methylamine solution for 25 percent aqueous ammonia solution in Example 1 F., the compound is obtained with a melting point of 161.5-163C. (decomp.) after recrystallization from ethanol.

B. 4-Anilino-5-methylcarbamyl-3-nitrobenzoic acid.

By substituting ethyl 4-anilino-5-methylcarbamyl- 3-nitrobenzoate for ethyl 4-anilino-5-carbamyl-3- nitrobenzoate in Example 1 G., and reducing the refluxing time to 45 minutes, the compound is obtained with a melting point of 164-166C., (decomp.) when recrystallized from ethanol/water. The compound crys' tallizes with one mole of water.

7 C. 3-Amino-4-anilino-S-methylcarbamyl-benzoic acid.

By substituting 4-ani1ino-5-methylcarbamyl-3- nitrobenzoic acid for 4-anilino-5-carbamyl-3- nitrobenzoic acid in Example 1 H., the compound is obtained with a melting point of 250-250,5C. (decomp.) after recrystallization from ethanol (99.9 percent) and drying in high vacuo at 80C. for 16 hours.

EXAMPLE 4.

3-Amino-4-anilino-5-dimethylcarbamylbenzoic acid A. Ethyl 4-aniIino-S-dimethylcarbamyl-3- nitrobenzoate.

By substituting a 40 percent aqueous dimethylamine solution for the 25 percent aqueous ammonia solution used in Example 1 F., and recrystallizing from ethanol, the compound is obtained as a monohydrate with a melting point of 99-103C. (decomp.).

B. 4-Ani1ino-5-dimethylcarbamyl-3-nitrobenzoic acid.

By substituting ethyl 4-anilino-3-dimethylcarbamyl- S-nitrobenzoate for ethyl 4-anilino-3-carbamyl-5- nitrobenzoate in Example 1 G., and reducing the refluxing time to 15 minutes, the compound is obtained with a melting point of 251252C. (decomp.) when recrystallized from aqueous ethanol.

C. 3-Amino-4-anilino-5-dimethylcarbamylbenzoic acid.

To a suspension of 4-anilino-5-dimethylcarbamyl-3- nitrobenzoic acid (6.7 g) inconcentrated hydrochloric acid (170 ml) zinc dust (30 g) is added in small portions while cooling and stirring. The precipitated zinc salts are removed by filtration and 6 N sodium hydroxide solution is added to the filtrate until pH 2-3. After cooling in a refrigerator the crystallized 3-amino-4- anilino-S-dimethylbenzoic acid is collected by filtration. The (crude) compound is dissolved in sodium hydrogen carbonate solution, treated with decalite and charcoal and precipitated by addition of acetic acid to the filtrate. After collection and recrystallization from ethanol/water the compound has a melting point of 247.5-248.5C.

EXAMPLE 4-Anilino-3-benzylamino-5-carbamylbenzoic acid.

A. Ethyl 4-anilino 3-benzylamino-5-carbamyl.benzoate.

To a suspension of 3-amino-4-anilino-5- carbamylbenzoic acid (1.35 g) in absolute ethanol (20 ml) benzylbromide (2.5 equivalents) is added. The stirred mixture is refluxed and refluxing continued for several hours after a solution has been achieved. Additional benzylbromide is added during the reaction and refluxing is continued. The esteriflcation and benzylation processes are controlled by thin layer chromatography. If necessary, this operation is repeated several times. After cooling, the precipitated ethyl 4-anilino-3- benzylamino-S-carbamylbenzoate is isolated by filtration. After recrystallization from 99 percent ethanol it has a melting point of 201203C.

B. 4-Anilino-3-benzylamino-5-carbamylbenzoic acid.

A stirred suspension of ethyl 4-anilino-3- benzylamino-5-carbamylbenzoate 1.7 g) in 50 percent aqueous ethanol (50 ml) containing 1 N sodium hydroxide (1 equivalent) is refluxed for 2 hours. After cooling. the 4-anilino-3-benzylamino-5- carbamylbenzoic acid is precipitated by addition of acetic acid, collected and recrystallized from isobutanol. The melting point is 272-274C. (decomp.)

EXAMPLE 6 4-Ani1ino-3-n-butylamino-5-carbamylbenzoic acid.

A. n-Butyl 4-anilino-3-n-butylamino-5-carbamylbenzoate.

A mixture of 3-amino-4-anilino-5-carbamylbenzoic acid (2.45 g), n-butanol (37 ml) and n-butyliodide (6.1 ml) is refluxed for 1 day while stirring. Then nbutyliodide (0.5 ml) is added and heating and stirring is continued for 3 days. The n-butyliodide addition is repeated and heating and stirring continued for one day more. The reaction mixture is evaporated in vacuo. and the residue is extracted with boiling cyclohexane ml). n-Butyl 4-anilino-3-n-butylamino-S-carbamylbenzoate crystallizes on cooling. After recrystallization from cyclohexane the compound has a melting point of 143C. The compound crystallizes with a A mole of cyclohexane.

B. 4-Anilino-3-n-butylamino-5-carbamylbenzoic acid.

A stirred suspension of n-butyl 4-anilino-3-nbutylamino-5-carbamy1benzoate (0.55 g) in water (10 ml) containing 1 N sodium hydroxide (1 equivalent) and ethanol (2 ml) is refluxed for 45 minutes. After cooling, the 4-anilino-3-n-butylamino-5- carbamylbenzoic acid is precipitated by addition of acetic acid, collected and recrystallized from ethanol. The melting point is 260261C. (decomp.).

EXAMPLE 7 4-Anilino-3-benzylamino-S-methylcarbamylbenzoic acid.

A. Ethyl 4-anilino-3-benzylamino-5-methylcarbamylbenzoate.

By substituting 3-amino-4-anilino-5-methylcarbamylbenzoic acid for 3-amino-4-ani1ino-5-carbamylbenzoic acid in Example 5 A., the compound is obtained with a melting point of 140.5142C. after recrystallization from aqueous ethanol.

B. 4-Anilino-3-benzylamino-S-methylcarbamylbenzoic acid.

By substituting ethyl 4-anilino-3-benzylamino-5- methylcarbamylbenzoate for n-butyl 4-anilino3-nbutylamino-5-carbamylbenzoate in Example 6 B. and extending the refluxing time to 1 hour, the compound is obtained with a melting point of 279-281C. (decomp.) after recrystallization from acetic acid/water.

EXAMPLE 8 4-Anilino-3-benzylamino-S-dimethylcarbamylbenzoic acid A. Ethyl 4-anilino-3-benzylamino-5-dimethylcarbamylbenzoate.

By substituting 3-amino-4-anilino-S-dimethylcarbamylbenzoic acid for 3-amino-4-anilino5- carbamylbenzoic acid in Example 5 A., the compound is obtained with a melting point of l62163C. after recrystallization from aqueous ethanol.

B. 4-Anilino-3-benzylamino-S-dimethylcarbamylbenzoic acid.

By substituting ethyl 4-anilino-3-benzylamino-5- dimethylcarbamylbenzoate for n-butyl 4-anilino-3-nbutylamin0-5-carbamylbenzoate in Example 6 B. and extending the refluxing time to 1.5 hours, the compound is obtained with a melting point of 9 254-254.5C. (decomp.) after recrystallization from ethanol.

EXAMPLE 9 3-Benzylamino-5-carbethoxy-4-phenylthiobenzoic acid.

A. -Nitro-4-phenylthioisophthalic acid.

4-chloro-5-nitroisophthalic acid (24.6 g) is dissolved in l N sodium hydrogen carbonate (300 ml), and thiophenol l l g) is added. The mixture is kept at approximately 85C. for 3.5 hours, while stirring. After cooling, 5-nitro-4-phenylthioisophthalic acid is precipitated by addition of concentrated hydrochloric acid. The compound is crystallized from aqueous ethanol and thereafter obtained as a monohydrate with a melting point of 235-236C.

B. 5-Amino-4-phenylthioisophthalic acid.

To a solution of 5-nitro-4-phenylthioisophthalic acid (25 g) in aqueous ammonia (300 ml containing 12.5 percent NHg), a solution of ferrous sulfate (1 50 g FeSO4, 7 H O) in hot water is added, and the reaction mixture is heated on a steam bath for 30 minutes. After addition of filteraid the mixture is filtered and the filtercake washed twice with hot water. From the filtrate 5- amino-4-phenylthioisophthalic acid is precipitated by addition of concentrated hydrochloric acid until pH 2. After recrystallization from aqueous ethanol the compound is obtained with a melting point of 235-236C.

C. Diethyl 3-benzylamino-4-phenylthioisophthalate.

A mixture of 5-amino-4-phenylthioisophthalic acid (15 g), benzyl bromide (25 g) and dry ethanol (300 ml) is refluxed, while stirring. Refluxing is continued for 2 days while after 6, 30, and 36 hours additional benzyl bromide (7.5 ml each time) is added. Thereafter the reaction mixture is evaporated in vacuo, and the resi due is triturated with diethyl ether (1 l) precipitating crude diethyl S-benzylamino-4-phenylthioisophthalate hydrobromide. The salt is collected by suction and washed with diethyl ether. From this salt the free benzylaminodiester is liberated by stirring in 0.5 N sodium hydrogen carbonate (350 ml) solution for 18 hours at room temperature. The diethyl 5-benzylamino-4- phenylthioisophthalate is collected by suction and recrystallized from ethanol. The compound is obtained with a melting point of 60C.

D. 3-Benzylamino-5-carbethoxy-4- phenylthiobenzoic acid.

To a solution of diethyl 5-benzylamino-4-phenylthioisophthalate (4.36 g) in ethanol (50 ml) 1 N sodium hydroxide is added. The reaction mixture is heated on a steam bath for 45 minutes. After evaporation in vacuo, the resulting residue is redissolved in a mixture of diethyl ether (25 ml) and water (25 ml). From the aqueous layer 3-benzylamino-5-carbethoxy-4- phenylthiobenzoic acid is precipitated by addition of 1 N hydrochloric acid ml). After recrystallization twice from acetone/petroleum ether, the compound is obtained with a melting point of 170171C.

EXAMPLE l0 3-Benzylamino-5-carbamyl-4-phenylthiobenzoic acid.

A solution of 3-benzylamino-5-carbethoxy-4- phenylthiobenzoic acid (0.6 g) in aqueous ammonia ml containing percent NH is left for 15 days at room temperature. The precipitated ammonium salt of 3-benzylamino-5-carbamyl-4-phenylthiobenzoic acid is collected by filtration and washed with aqueous ammonia. The salt is dissolved in hot water (65 ml) and the acid liberated by the addition of 1 N hydrochloric acid until pH 2. The compound has a melting point of 229-230C.

EXAMPLE ll 3-Benzylamino-5-methylcarbamyl-4- phenylthiobenzoic acid.

A solution of 3-benzylamino-5carbethoxy-4- phenylthiobenzoic acid (0.4 g) in aqueous methylamine (8 ml containing 35 percent CH Nl-l is left for 3 days. The excess of methylamine is distilled off, and after addition of water (20 ml), 3-benzylamino-5- methylcarbamyl-4-phenylthiobenzoic acid is precipitated by the addition of 4 N hydrochloric acid until pH 2. After recrystallization from ethanol, the compound is obtained with a melting point of 250252C.

EXAMPLE l2.

3-Benzylamino-5-ethylcarbamyl-4- phenylthiobenzoic acid.

A solution of 3-benzylamino-5-carbethoxy-4- phenylthiobenzoic acid (0.5 g) in aqueous ethylamine (5 ml containing percent C HsNH is left for 4 weeks. Excess of ethylamine is distilled off and 4- benzylamino-5-ethylcarbamyl-4-phenylthiobenzoic acid precipitated by the addition of l N hydrochloric acid. After recrystallization from ethanol the compound is obtained with a melting point of 225226C.

EXAMPLE l3 3-Benzylamino-5-(B-hydroxyethylcarbamyl)-4- phenylthiobenzoic acid.

A mixture of 3-benzylamino-5-carbethoxy-4- phenylthiobenzoic acid (0.5 g) and ethanolamine (5 ml) is kept at l25-l 30C. for 20 hours. After cooling, ethanol (5 ml) and water (20 ml) is added, and 3- benzylamino-5-(B-hydroxyethylcarbamyl)-4- phenylthiobenzoic acid precipitated by the addition of 4 N hydrochloric acid. After recrystallization from ethanol the compound is obtained with a melting point of 236237C.

EXAMPLE l4 3-Benzylamino-S-carbethoxy-4-p-chlorophenylthiobenzoic acid A. 4-p-Chlorophenylthio-5-nitroisophthalic acid.

A mixture of 4-chloro-S-nitroisophthalic acid (21.3 g), p-chlorothiophenol (7.5 g) and l N sodium hydrogen carbonate is kept at C. for 80 hours. After cooling, the 4-p-chlorophenylthio-5-nitroisophthalic acid is precipitated by the addition of concentrated hydrochloric acid. After collection and recrystallization from aqueous ethanol, the compound is obtained with a melting point of 253C. (decomp.).

B. 5-Amino-4-p-chlorophenylthioisophthalic acid.

By substituting in example 9 B. 4-p-chlorophenylthionitroisophthalic acid for 5-nitro-4-phenylthioisophthalic acid, 5-amino-4-p-chlorophenylthioisophthalic acid is obtained with a melting point of 235236C.

C. Diethyl 5-benzylamino-4-(p-chlorophenylthio)- isophthalate.

A mixture of 5-amino-4-(p-chlorophenylthio)- isophthalic acid (6.5 g), benzyl bromide (5.5 ml) and dry ethanol ml) is refluxed, while stirring. Refluxing is continued for 2 days, while after 6, 20 and 36 hours additional benzyl bromide (4 ml each time) is added. Thereafter the reaction mixture is evaporated in vacuo, and the residue triturated with l N sodium hydrogen carbonate. The oily reaction product is extracted with diethyl ether. The extract is evaporated in vacuo and the residue crystallized by the addition of petroleum ether. The diethyl 'benzylamino-4-(pchlorophenylthio)-isophthalate is obtained with a melting point of 97C after recrystallization from ethanol.

D. 3-Benzylamino-5-carbethoxy-4-(p-chlorophenylthio)-benzoic acid.

A mixture of diethyl 5-benzylamino-4-(pchlorophenylthio)-isophthalate (3.5 g), ethanol (40 ml) and l N sodium hydroxide (7.4 ml) is heated on a steam bath for 45 minutes. The ethanol is distilled off in vacuo, and water (50 ml) is added. On cooling, the sodium salt of 3-benzylamino-5-carbethoxy-4-(pchlorophenylthio)-benzoic acid crystallizes. The salt is collected by filtration and washed with ice-cooled water, and recrystallized from water (25 ml). The sodium salt is redissolved in hot water and the 3-benzylamino- 5-carbethoxy-4-(p-chlorophenylthio)-benzoic acid precipitated by the addition of 1 N hydrochloric acid until pH 2. The compound is obtained with a melting point of l82l83C.

EXAMPLE l5 3-Benzylamino-5-carbamyl-4-p-chlorophenylthiobenzoic acid.

By replacing in example 10, 3-benzylamin0-5- carbethoxy-4-phenylthiobenzoic acid with 3- benzylamino-5-carbethoxy-4-p-chlorophenylthiobenzoic acid, 3-benzylamino-5-carbamyl-4-p-chlorophenylthiobenzoic acid is obtained with a melting point of 253 254C.

EXAMPLE 16 B-Benzylamino-5-carbethoxy-4-phenoxybenzoic acid.

A. Diethyl 5-nitro-4-phenoxyisophthalate.

To a solution of potassium phenolate (28 g) in phenol (80 g), diethyl 4-chloro-5-nitroisophthalate (60.3 g) and copper powder (0.2 g) is added at 90C., while stirring. After stirring for 21 hours at 60C., the reaction mixture is slowly poured into water (1.4 1), while stirring. After stirring and cooling for several hours, the diethyl 5-nitro-4-phenoxyisophthalate is collected by suction and washed with water. After recrystallization from ethanol the compound is obtained with a melting point of 9899C.

B. Diethyl 5-amino'4-phenoxyisophthalate.

Diethyl 5-nitro-4-phenoxyisophthalate (36 g) is suspended in 99.9 percent ethanol (1500 ml) and hydrogenated after addition of a palladium-on-carbon catalyst (3 g catalyst, containing 10 percent Pd). When the hydrogen uptake becomes negligible, the catalyst is removed by filtration and the diethyl 5-amino-4- phenoxyisophthalate is precipitated from the filtrate by the addition of water. After crystallizing in a refrigerator, the compound is collected by suction, washed with 50 percent aqueous ethanol and recrystallized from 60 percent aqueous ethanol. It has a melting point of 73.575C.

C. Diethyl 5-benzylamino-4-phenoxyisophthalate.

By replacing in example 9C 5-amino-4-phenylthioisophthalic acid with diethyl 5-amino-4- phenoxyisophthalate and by decreasing the amount of 12 diethyl ether to ml, diethyl 5-benzylamino-4- phenoxyisophthalate is obtained with a melting point of 63-65C.

D. 3-Benzylamino-S-carbethoxy-4-phenoxybenzoic acid.

By replacing diethyl S-benzylamino-4-phenylthioisophthalate with diethyl 5-benzylamino-4- phenoxyisophthalate(4.2 g) in example 9D and recrystallization of the crude product from aqueous ethanol and acetone/petroleum ether, 3-benzylamino-5- carbethoxy-4-phenoxybenzoic acid is obtained with a melting point of l59-l60C.

EXAMPLE 1? 3-Benzylamino-5-carbamyl-4-phenoxybenzoic acid.

By replacing in example 10, 3-benzylamino-5- carbethoxy-4-phenylthiobenzoic acid with 3- benzylamino-5-carbethoxy-4-phenoxybenzoic acid (0.6 g), 3-benzylamino-S-carbamyl-4-phenoxybenzoic acid is obtained with a melting point of 245-247C after drying in vacuo.

EXAMPLE l8 3-Benzylamino-5-methylcarbamyl-4- phenoxybenzoic acid.

By replacing in example I l, 3-benzylamino-5- carbethoxy-4-phenylthiobenzoic acid with 3- benzylamino-5-carbethoxy-4-phenoxybenzoic acid, 3- benzylamino-5-methylcarbamyl-4phenoxybenzoic acid is obtained with a melting point of 252-254C.

EXAMPLE l9 3-Benzylamino-4-phenoxy-5-propylcarbamylbenzoic acid.

A mixture of 3-benzylamino-5-carbethoxy-4- phenoxybenzoic acid (0.5 g) and n-propylamine (10 ml) is refluxed for 10 days. The excess of propylamine is distilled off in vacuo, and the residue is dissolved in hot water (25 ml). The resulting solution is treated with decolourizing carbon and filtered. From the still hot filtrate 3-benzylamino-4-phenoxy-5-propylcarbamylbenzoic acid is precipitated by the addition of l N hydrochloric acid until pH 2. The compound is collected by suction and is obtained with a melting point of 2l7218C. after recrystallization from aqueous ethanol and drying.

EXAMPLE 20 3-Benzylamino-5-n-butylcarbamyl-4- phenoxybenzoic acid.

By replacing n-propylamine with n-butylamine (5 ml) in example 19 and by decreasing the reaction time to 3 days, the 3-benzylamino-5-n-butylcarbamyl-4- phenoxybenzoic acid is obtained with a melting point of l99-200.5C.

' EXAMPLE 21 3-Benzylamino-5-(Z-methoxyethylcarbamyl)-4- phenoxybenzoic acid.

By replacing n-propylamine with 2- methoxyethylamine in example 19 the 3-benzylamino- 5-(2-methoxyethylcarbamyl)-4-phenoxybenzoic acid is obtained with a melting point of l64-l66C.

EXAMPLE 22 3-Amino-5-carbamyl-4-phenoxybenzoic acid. A. 3-Amino-5-carbethoxy-4-phenoxybenzoic acid.

Diethyl amino-4-phenoxyisophthalate g) is dissolved in 99.9 percent ethanol (75 ml) by warming and a solution of 88 percent potassium hydroxide (2 g) in 99.9 percent ethanol (25 ml) is added during half an hour by vigorous stirring. Then the reaction mixture is refluxed for 1.5 hours, while stirring. After cooling, excess of starting material is precipitated by the addition of water and is removed by filtration after standing in a refrigerator. The filtrate is adjusted to pH 3 by the addition of acetic acid, and the precipitated 3-amino-5- carbethoxy-4-phenoxybenzoic acid is collected by suction and washed with water. After recrystallization from aqueous ethanol the compound has a melting point of l7l.5-l72.5C.

B. 3-Aminc-5'carbamyl-4-phenoxybenzoic acid.

A solution of 3-amino-5-carbethoxy-4- phenoxybenzoic acid (3 g) in 25 percent aqueous ammonia solution (50 ml) is kept dark at room temperature for 8 days. The reaction mixture is evaporated to dryness in vacuo and the residue dissolved in acetic acid (50 ml). The 3-amino-5-carbamyl-4- phenoxybenzoic acid crystallizes by the addition of water (50 ml) to the solution on cooling. After collection by suction and recrystallization from 50 percent aqueous ethanol the compound has a melting point of 249250C. (decomp.).

EXAMPLE 23 3-Amino-5methylcarbamyl-4-phenoxybenzoic acid.

A solution of 3-amino-5-carbethoxy-4- phenoxybenzoic acid (6 g) in aqueous methylamine (100 ml containing 35 percent CHaNHg) is stirred at room temperature for 17 hours and subsequently evaporated in vacuo. The oily residue is treated with 50 percent aqueous acetic acid (100 ml), the precipitated 3- amino-Smethylcarbamy1-4-phenoxybenzoic acid is collected by suction and washed with water. After recrystallization from aqueous ethanol the compound has a melting point of 209-209.5C.

EXAMPLE 24 3-Benzylamino-5-methylcarbamyl-4- phenoxybenzoic acid.

To a suspension of 3-amino-5-methylcarbamyl-4- phenoxybenzoic acid (1.8 g) in acetic acid (100 ml), benzaldehyde (0.73 g) is added. After the addition of platinum oxide (80 mg) and a catalytic amount of p-toluenesulfonic acid, the reaction mixture is hydrogenated at room temperature and 1.1 atmosphere hydrogen pressure until the hydrogen uptake becomes negligible. Then the catalyst is removed by filtration and the filtrate diluted with water to precipitate 3- benzylamino-S-methylcarbamyl-4-phenoxybenzoic acid. The compound is collected by filtration and washed with water. After recrystallization from ethanol/water, the compound is obtained with a melting point of 253-255.5C. (decomp.)

EXAMPLE 25 3-Amino-5methylcarbamyl4-p-toloxybenzoic acid.

A. Diethyl 5-nitro-4p-toloxyisophthalate.

To a mixture of potassium p-cresolate (1.6 g) and pcresol (9 g), diethyl 4-chloro-5nitroisophthalate is added in portions at 90C. After addition of copper powder (0.02 g) the reaction mixture is stirred at 60C. for 26 hours. The resulting melt is poured into l N potassium hydroxide (100.5 ml). After stirring and cooling it is extracted twice with diethyl ether ml). The organic extract is washed with water, dried over MgSO, and evaporated in vacuo. Aqueous ethanol is added to the residue to effect crystallization. The diethyl 5-nitro-4-p-toloxyisophthalate is collected and recrystallized from ethanol. The compound is obtained with a melting point of 5759C.

B. Diethyl 5amino-4p-toloxyisophthalate.

By replacing in example 16 B the solution of diethyl 5-nitro-4-phenoxyisophthalate in ethanol with a solution of diethyl 5nitro-4-p-toloxyisophthalate (37.3 g) in acetic acid (250 ml). diethyl 5-amino-4-ptoloxyisophthalate is obtained with a melting point of 8082C.

C. 3-Amino-5carbethoxy-4-p-toloxybenzoic acid.

By replacing in example 9 D, diethyl S-benzylamino- 4-phenylthioisophthalate, ethanol, and sodium hydroxide with diethyl 5amino-4-p-toloxyisophthalate (10.3 g), ethanol ml), and 1 N sodium hydroxide (30 ml), 3-aminc-5carbethoxy-4-p-toloxybenzoic acid is obtained with a melting point of l72-l73.5C.

D. 3Amino-S-methylcarbamyl-4-p-toloxybenzoic acid.

A mixture of 3-amino-5carbethoxy-4-ptoloxybenzoic acid (1.75 g) and aqueous methylamine (17.5 ml containing 35 percent of methylamine) is left to stand for 60 hours. Excess of methylamine is distilled off and 3amino-Smethylcarbamyl-4-p-toloxybenzoic acid precipitated by the addition of 1 N hydrochloric acid until pH 3. After recrystallization from aqueous ethanol the compound is obtained with a melting point of 222-223.5C.

EXAMPLE 26 3Benzylamino-Smethylcarbamyl-4p-toloxybenzoic acid.

A suspension of 3amino-4-methylcarbamyl-4-ptoloxybenzoic acid (0.45 g) in water 15 ml) is adjusted to a pH of 7.5 by the addition of 2 N sodium hydroxide. To the resulting solution, benzyl bromide (0.26 g) is added and, while stirring the pH is kept at 7.5 by automatic titration with sodium hydroxide. After the base comsumption has become negligible, 1 N hydrochloric acid is added until pH 2 to precipitate 3-benzylamino- 5methylcarbamyl4-p-toloxybenzoic acid. After recrystallization from aqueous ethanol and drying in vacuo, the compound is obtained with a melting point of 26l263C.

What is claimed is:

1. Compounds of the general formula I in which X is S--; R is selected from the group consisting of hydrogen and aliphatic hydrocarbon radicals with from one to four carbon atoms; R is selected from the group consisting of hydrogen, saturated and unsaturated, straight and branched aliphatic hydrocarbon radicals with from one to six carbon atoms; R;, is selected from the group consisting of saturated and unsaturated, straight and branched aliphatichydrocarbon radicals with from one to six carbon atoms, and aryl.

5. A compound according to claim 1, in which R is hydrogen, and R is a methyl group.

6. A compound as claimed in claim 1, in which R and R are hydrogen, R is benzyl, R4 is phenyl, and X is sulphur, and pharmaceutically acceptable salts and esters thereof.

7. A compound as claimed in claim 1, in which R. is hydrogen, R is methyl, R is benzyl, R is phenyl. and X is sulphur, and pharmaceutically acceptable salts and esters thereof. 

1. COMPOUNDS OF THE GENERAL FORMULA I
 2. A compound as claimed in claim 1, in which R3 is a benzylgroup.
 3. A compound according to claim 1, in which R4 is a phenyl group.
 4. A compound according to claim 1, in which R1 and R2 are hydrogen.
 5. A compound according to claim 1, in which R1 is hydrogen, and R2 is a methyl group.
 6. A compound as claimed in claim 1, in which R1 and R2 are hydrogen, R3 is benzyl, R4 is phenyl, and X is sulphur, and pharmaceutically acceptable salts and esters thereof.
 7. A compound as claimed in claim 1, in which R1 is hydrogen, R2 is methyl, R3 is benzyl, R4 is phenyl, and X is sulphur, and pharmaceutically acceptable salts and esters thereof. 